Laurie Zawertailo

Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans

To assess the pharmacologie effects and abuse liability of bretazenil, a partial benzodiazepine agonist, and compare them to the short‐term effects of diazepam and alprazolam over a range of doses.

Monoamine Oxidase A Binding in the Prefrontal and Anterior Cingulate Cortices During Acute Withdrawal From Heavy Cigarette Smoking

CONTEXT Greater prefrontal cortex and anterior cingulate cortex monoamine oxidase A (MAO-A) binding is associated with depressed mood. Substances in cigarette smoke, such as harman, inhibit MAO-A, and cigarette withdrawal is associated with depressed mood. Dysphoria during cigarette withdrawal predicts relapse. It is unknown whether MAO-A binding increases during early cigarette withdrawal. OBJECTIVES To measure prefrontal and anterior cingulate cortex MAO-A binding during acute cigarette withdrawal and to assess the relationship with smoking severity, plasma levels of harman, and severity of depression. DESIGN Study via positron emission tomography of healthy control and cigarette-smoking individuals. PATIENTS Twenty-four healthy nonsmoking and 24 otherwise healthy cigarette-smoking individuals underwent positron emission tomography with harmine labeled with carbon 11. Healthy nonsmoking individuals underwent scanning once. Cigarette-smoking individuals underwent scanning after acute withdrawal and after active cigarette smoking. Cigarette smoking was heavy (≥25 cigarettes per day) or moderate (15-24 cigarettes per day). SETTING Tertiary care psychiatric hospital. MAIN OUTCOME MEASURE An index of MAO-A density, MAO-A V(T), was measured in the prefrontal and anterior cingulate cortices. RESULTS In heavy-smoking individuals, prefrontal and anterior cingulate cortex MAO-A V(T) was greater during withdrawal (23.7% and 33.3%, respectively; repeated-measures multivariate analysis of variance, F(1,22) = 25.58, P < .001). During withdrawal from heavy smoking, prefrontal and anterior cingulate cortex MAO-A V(T) was greater than in healthy controls (25.0% and 25.6%, respectively; multivariate analysis of variance, F(2,33) = 6.72, P = .004). The difference in MAO-A V(T) in the prefrontal cortex and anterior cingulate cortex between withdrawal and active, heavy smoking covaried with change in plasma harman levels in the prefrontal cortex and anterior cingulate cortex (multivariate analysis of covariance, F(1,10) = 9.97, P = .01). The change in MAO-A V(T) between withdrawal and active, heavy smoking also covaried with severity of depression (multivariate analysis of covariance, F(1,10) = 11.91, P = .006). CONCLUSIONS The increase in prefrontal and anterior cingulate cortex MAO-A binding and associated reduction in plasma harman level represent a novel, additional explanation for depressed mood during withdrawal from heavy cigarette smoking. This finding resolves a longstanding paradox regarding the association of cigarette smoking with depression and suicide and argues for additional clinical trials on the effects of MAO-A inhibitors on quitting heavy cigarette smoking.

Comparative abuse liability of sertraline, alprazolam, and dextroamphetamine in humans

Sertraline is an effective antidepressant acting as a selective serotonin reuptake inhibitor. The subjective and behavioral effects of sertraline were studied and compared with the effects of alprazolam and dextroamphetamine in a within-subject, randomized, double-blind study in 20 volunteers aged 18 to 46 years. These subjects were experienced but nondependent users of central nervous system depressants who had the ability to reliably distinguish secobarbital, 150 mg, from placebo and to report positive subjective effects of secobarbital in an experimental setting. The following drug conditions were tested: sertraline, 100 and 200 mg; alprazolam, 1 mg; dextroamphetamine, 10 mg; and placebo. Drug effects were assessed with an objective test of psychomotor performance, subject-rated questionnaires, and observer-rated scales. Both alprazolam and dextroamphetamine were distinguishable from placebo on most measures, but sertraline produced effects discernable from placebo on only a few measures. At 1 hour postdrug administration, dextroamphetamine and alprazolam produced positive effects on several measures of elation, euphoria, and drug liking greater than placebo and both doses of sertraline. In contrast, sertraline produced higher scores on measures of dysphoria and physical unpleasantness than did the other drug conditions. Observer ratings of satisfaction with the drug and other pharmacologic effects were consistent with these findings. Results from this study indicate that sertraline, at the doses tested, does not possess the behavioral effects profile considered to be indicative of abuse potential when compared with alprazolam and dextroamphetamine.

Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism : A pilot study

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan. CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95+/-0.5% for EMs vs. 86+/-6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan.

Dopaminergic activity in depressed smokers: a positron emission tomography study.

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [11C]‐raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d‐amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [11C]‐raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d‐amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non‐smokers). Striatal [11C]‐raclopride binding potential was measured before and after d‐amphetamine administration. Depressed smokers had a lower baseline [11C]‐raclopride binding potential compared with both control non‐smokers (P < 0.007) and depressed non‐smokers (P < 0.001). There was a main effect of smoking status on amphetamine‐induced change in [11C]‐raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d‐amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non‐smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d‐amphetamine‐induced changes in [11C]‐raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients. Synapse 63:681–689, 2009.

Elevation of dopamine induced by cigarette smoking: novel insights from a [11C]-+-PHNO PET study in humans.

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine’s addictive potential. Here, we used PET and [11C]-(+)-PHNO ([11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [11C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [11C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [11C]-(+)-PHNO binding in D2 and D3-rich areas (−12.0 and −15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [11C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.

Comparative abuse liability and pharmacological effects of meprobamate, triazolam and butabarbital

Implementation of regulations to control the prescribing of benzodiazepines in New York State in 1989 resulted in a 55% decrease in benzodiazepine prescribing, with a concomitant increase in the rates of prescribing older sedativehypnotic compounds such as butabarbital (30% increase) and meprobamate (125% increase). In a double-blind, crossover, placebo-controlled study, we compared the behavioral and pharmacological effects of triazolam, meprobamate, and butabarbital in 14 recreational drug users. Placebo and three doses each of triazolam, meprobamate, and butabarbital were administered to each subject in a random order. Objective tests (motor performance, concentration) and subjective response questionnaires measured drug effects. Triazolam, meprobamate, and butabarbital showed comparable negative dose-response slopes on the objective measures. On the basis of these objective data, equivalent doses for the three compounds were determined to be as follows: 0.5 mg triazolam = 2,400 mg meprobamate = 400 mg butabarbital. Subjective effects data on equivalent doses show that butabarbital produced the highest peak score on Cole/ARCI Abuse Potential, ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG), and “drug strength” scales. Triazolam and butabarbital produced equivalent results on ARCI Morphine Benzedrine Group (MBG), Cole/ARCI Euphoria, and “drug liking” scales. Meprobamate was indistinguishable from placebo on euphoria and abuse potential scales. Behavioral economics analysis indicated a price crossover point two times higher for butabarbital (400 mg) than for any other drug condition. These data indicate a comparative abuse liability of butabarbital > triazolam ≥ meprobamate, suggesting that the prescribing restrictions on benzodiazepines had little net benefit on abuse risk in the population and may have increased the risk of overdose morbidity and mortality.

Effect of metabolic blockade on the psychoactive effects of dextromethorphan

Variation in the activity of cytochrome P450 2D6 (CYP2D6) affects the pharmacokinetics and effectiveness of dextromethorphan (DM), because it controls the production of dextrorphan, an active metabolite, with higher affinity for the NMDA receptor than the parent compound. This study examined whether pharmacological inhibition of CYP2D6 activity with quinidine would mimic the genetic mutation and thus also alter the psychoactive effects of DM.

Enhanced smoking cue salience associated with depression severity in nicotine-dependent individuals: a preliminary fMRI study

The association between cigarette smoking and depression has been well documented; however, little research has been done to elucidate the neurobiological substrates of this highly prevalent comorbidity. We used multiple linear regression analysis to evaluate the relationship between depression severity as assessed by the Hamilton Depression Rating Scale (HAMD) and blood oxygen level-dependent (BOLD) responses to visual smoking cues in drug-free nicotine-dependent smokers (n=18). Two functional magnetic resonance imaging (fMRI) scans were completed over a single study day, following overnight smoking abstinence (pre-smoking scan) and after cigarette reinstatement (post-smoking scan). During the pre-smoking scan positive correlations between BOLD activity and HAMD scores were observed in areas of the mesocorticolimbic dopaminergic system [inferior frontal gyrus, middle frontal gyrus (MFG), hippocampus (HC), anterior cingulate gyrus] and areas of the visuospatial attention circuit (medial occipital lobe, middle cingulate cortex, superior frontal gyrus, angular gyrus). During the post-smoking scan positive correlations were observed in areas of the brain implicated in drug expectancy (MFG), memory (HC), attentional motivation (posterior cingulate cortex), and visual processing and attention (precuneus). These preliminary findings demonstrate that smokers with higher depression severity attribute greater incentive salience to smoking-related cues and this is especially pronounced during periods of acute abstinence. Such enhanced salience of smoking cues, even after smoking a cigarette, may play a critical role both in the maintenance of smoking in depression and in greater levels of nicotine dependence seen in this patient population.

Individualized smoking cessation treatment in an outpatient setting: Predictors of outcome in a sample with psychiatric and addictions co-morbidity

OBJECTIVE Patients with psychiatric disorders have higher rates of smoking and greater difficulty quitting smoking. However, few studies have compared patients with schizophrenia or schizoaffective disorders to patients with other psychiatric diagnoses without psychosis, addressing ability to quit and differences in treatment characteristics. METHOD A retrospective chart review was conducted on a sample of 165 cigarette smokers admitted to an outpatient smoking cessation clinic located in a large inner-city psychiatric hospital. Patients with schizophrenia and schizoaffective disorder (n=55) were matched for age and sex at a ratio of 1:2 with a comparison group without psychosis (n=110) from the same clinic. Primary outcomes of interest were quit status (7-day point prevalence) and significant reduction in cigarettes per day (>or=50% but not quit) at final treatment session. RESULTS There were no significant differences between groups for end-of-treatment quit rate or significant reduction (>or=50%) in cigarettes per day. Patients with schizophrenia made significantly more visits to the clinic and were in treatment for a longer period of time. A greater number of individual treatment sessions and being male were the most significant predictors of cessation. CONCLUSION Patients with schizophrenia were as likely to quit smoking as a comparison group of patients with a high rate of other psychiatric comorbidities without psychosis. Findings suggest treatment success in this population requires an extended number of clinic visits, group therapy, and possibly higher doses of nicotine replacement.